Cystic Fibrosis Transmembrane Conductance Regulator Deficiency Exacerbates Islet Cell Dysfunction After β-Cell Injury

Stalvey, Michael S.; Müller, Christian; Schatz, Desmond; Wasserfall, Clive; Campbell-Thompson, Martha; Theriaque, Douglas W.; Flotte, Terence R.; Atkinson, Mark A.

doi:10.2337/db05-1647

Cited by 39 publications

(34 citation statements)

References 26 publications

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“…Alternatively, a more direct role for CFTR in the regulation of the endocrine pancreas has been proposed (35,36). Our above results demonstrating a correlation between hyperglycemia onset and histopathologic damage to the CF pancreas supports the bystander damage hypothesis (Figures 1-3), but does not disprove potential involvement of CFTR in regulating the endocrine pancreas.…”

Section: Figuresupporting

confidence: 77%

“…Furthermore, to our knowledge, no clinical studies have evaluated CF glucose abnormalities in the first years of life. Cftr-knockout mice demonstrate enhanced sensitivity to low-dose streptozotocin-induced hyperglycemia, but are euglycemic in the absence of streptozotocin (35,36). The recent development of CFTR-knockout models in the pig and ferret provides new avenues for investigating the pathogenesis of CFRD.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets

Olivier¹,

Yi²,

Sun³

et al. 2012

J. Clin. Invest.

122

143

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Diabetes is a common comorbidity in cystic fibrosis (CF) that worsens prognosis. The lack of an animal model for CF-related diabetes (CFRD) has made it difficult to dissect how the onset of pancreatic pathology influences the emergence of CFRD. We evaluated the structure and function of the neonatal CF endocrine pancreas using a new CFTR-knockout ferret model. Although CF kits are born with only mild exocrine pancreas disease, progressive exocrine and endocrine pancreatic loss during the first months of life was associated with pancreatic inflammation, spontaneous hyperglycemia, and glucose intolerance. Interestingly, prior to major exocrine pancreas disease, CF kits demonstrated significant abnormalities in blood glucose and insulin regulation, including diminished first-phase and accentuated peak insulin secretion in response to glucose, elevated peak glucose levels following glucose challenge, and variably elevated insulin and C-peptide levels in the nonfasted state. Although there was no difference in lobular insulin and glucagon expression between genotypes at birth, significant alterations in the frequencies of small and large islets were observed. Newborn cultured CF islets demonstrated dysregulated glucose-dependent insulin secretion in comparison to controls, suggesting intrinsic abnormalities in CF islets. These findings demonstrate that early abnormalities exist in the regulation of insulin secretion by the CF endocrine pancreas. IntroductionCystic fibrosis (CF) is caused by defects in the CF transmembrane conductance regulator (CFTR) chloride channel. Cystic fibrosisrelated diabetes (CFRD) is a common complication of CF and affects 20%-25% of adolescents and 40%-50% of individuals over 30 years of age (1,2). CFRD is associated with worsening clinical status, including reduced pulmonary function, increased frequency of pulmonary exacerbations, and a decline in nutritional status (3-7). Furthermore, CFRD leads to increased mortality compared with CF patients without diabetes (4,8). Thus, early diagnosis and treatment are vital to improving clinical outcome of CFRD patients.While the pathophysiology of CFRD is multifactorial, delayed insulin secretion appears to be a key hallmark of disease progression (9-12), and the health of CF patients is improved by insulin therapy prior to and following diagnosis of overt diabetes (13,14). Partial insulin deficiency occurs in part due to islet loss associated with exocrine pancreas disease (15-18). However, CF pancreata at CFRD autopsy demonstrate that remaining islets contain roughly half the number of insulin-positive cells found in non-CF controls (17,18), and this degree of β cell loss is thought to be insufficient to explain diabetes (19). Thus, insulin deficiency in CFRD is relative and not absolute. All stages of CFRD are characterized by abnormalities in circulating insulin levels (10,12,20,21). Impaired first-phase insulin (IFPI) responses are common in CFRD patients, but also occur in approximately 50% of CF children with normal glucose tolerance (9). Cu...

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Section: Figuresupporting

confidence: 77%

Section: Introductionmentioning

confidence: 99%

Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets

Olivier¹,

Yi²,

Sun³

et al. 2012

J. Clin. Invest.

122

143

View full text Add to dashboard Cite

show abstract

“…This finding supports a function for CFTR in pancreatic islets where, in rats, investigators have identified CFTR mRNA (20). In mice made diabetic by streptozotocin, those who were CFTR-null (Ϫ/Ϫ) had higher blood glucose levels than other mice; the investigators concluded that islet dysfunction is inherent to the CFTR Ϫ/Ϫ state (21). CFTR has also been identified in the human hypothalamus, (22), where it may play a role in glucose regulation.…”

Section: Risk Factorssupporting

confidence: 58%

Genetic Determinants and Epidemiology of Cystic Fibrosis–Related Diabetes

et al. 2008

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OBJECTIVE -Longer survival of patients with cystic fibrosis has increased the occurrence of cystic fibrosis-related diabetes (CFRD). In this study we documented the incidence of CFRD and evaluated the association between mutations responsible for cystic fibrosis and incident CFRD, while identifying potential risk factors.RESEARCH DESIGN AND METHODS -This was a population-based longitudinal study of 50 cystic fibrosis speciality clinics in the U.K. Subjects included 8,029 individuals aged 0 -64 years enrolled in the U.K. Cystic Fibrosis Registry during 1996 -2005. Of these, 5,196 with data and without diabetes were included in analyses of incidence, and 3,275 with complete data were included in analyses of risk factors. Diabetes was defined by physician diagnosis, oral glucose tolerance testing, or treatment with hypoglycemic drugs.RESULTS -A total of 526 individuals developed CFRD over 15,010 person-years. The annual incidence was 3.5%. The incidence was higher in female patients and in patients with mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene in classes I and II. In a multivariate model of 377 cases of 3,275 patients, CFTR class (relative risk 1.70 [95% CI 1.16 -2.49], class I or II versus others), increasing age, female sex, worse pulmonary function, liver dysfunction, pancreatic insufficiency, and corticosteroid use were independently associated with incident diabetes.CONCLUSIONS -The incidence of CFRD is high in Britain. CFTR class I and II mutations increase the risk of diabetes independent of other risk factors including pancreatic exocrine dysfunction.

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“…Unlike previous reports where CFTR-deficient mice showed an exacerbation of STZ-induced hyperglycemia, our findings showed no difference between STZ-treated CFKO and WT mice (38). The rationale for these differences is likely a result in the variations of STZ treatment regimens.…”

Section: Discussioncontrasting

confidence: 56%

Hyperglycemia impedes lung bacterial clearance in a murine model of cystic fibrosis-related diabetes

Hunt

Zughaier

Guentert

et al. 2014

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Cystic fibrosisrelated diabetes (CFRD) is the most common comorbidity associated with cystic fibrosis (CF), impacting more than half of patients over age 30. CFRD is clinically significant, portending accelerated decline in lung function, more frequent pulmonary exacerbations, and increased mortality. Despite the profound morbidity associated with CFRD, little is known about the underlying CFRD-related pulmonary pathology. Our aim was to develop a murine model of CFRD to explore the hypothesis that elevated glucose in CFRD is associated with reduced lung bacterial clearance. A diabetic phenotype was induced in gut-corrected CF transmembrane conductance regulator (CFTR) knockout mice (CFKO) and their CFTR-expressing wild-type littermates (WT) utilizing streptozotocin. Mice were subsequently challenged with an intratracheal inoculation of Pseudomonas aeruginosa (PAO1) (75 l of 1-5 ϫ 10 6 cfu/ml) for 18 h. Bronchoalveolar lavage fluid was collected for glucose concentration and cell counts. A portion of the lung was homogenized and cultured as a measure of the remaining viable PAO1 inoculum. Diabetic mice had increased airway glucose compared with nondiabetic mice. The ability to clear bacteria from the lung was significantly reduced in diabetic WT mice and control CFKO mice. Critically, bacterial clearance by diabetic CFKO mice was significantly more diminished compared with nondiabetic CFKO mice, despite an even more robust recruitment of neutrophils to the airways. This finding that CFRD mice boast an exaggerated, but less effective, inflammatory cell response to intratracheal PAO1 challenge presents a novel and useful murine model to help identify therapeutic strategies that promote bacterial clearance in CFRD.cystic fibrosis-related diabetes; murine model; Pseudomonas; pneumonia; cystic fibrosis CYSTIC FIBROSIS (CF) is the most common inheritable lethal disorder among Caucasians (25). Although often primarily characterized by a progressive pulmonary decline due to frequent pulmonary exacerbations, the disease carries risk for numerous other comorbidities (27). More than 75% of adults with CF demonstrate some aberrancy in glucose regulation, for many of which constitutes a comorbidity termed cystic fibrosis-related diabetes (CFRD) (4,12,25). CFRD is now recognized as the most common comorbidity associated with CF, affecting more than 50% of patients over the age of 30 with increasing prevalence rates rising with increasing age (4,5,25). CFRD is punctuated by delayed insulin secretion, glucose dysregulation, and hyperglycemia (22-24, 34). Consequences of prolonged hyperglycemia can include significant microvascular complications similar to what is observed in other types of diabetes (36,40, 44). However, by far the most egregious insult to a patient with CFRD is the rapid decline in pulmonary function and increase in pulmonary exacerbations associated with onset of the disease (19). The inception of CFRD at any age accelerates pulmonary decline, as noted in multiple epidemiological studies documenting both dete...

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Cystic Fibrosis Transmembrane Conductance Regulator Deficiency Exacerbates Islet Cell Dysfunction After β-Cell Injury

Cited by 39 publications

References 26 publications

Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets

Abnormal endocrine pancreas function at birth in cystic fibrosis ferrets

Genetic Determinants and Epidemiology of Cystic Fibrosis–Related Diabetes

Hyperglycemia impedes lung bacterial clearance in a murine model of cystic fibrosis-related diabetes

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